Our laboratory uses biochemical, genetic, and transgenic methods to understand the normal and oncogenic properties of several genes implicated in neoplasia. Current activities address the following issues: (1) The functions of protein-tyrosine kinases. Members of three families of such kinases are under study. (a) Src, Hck, and other members of the Src family that have demonstrated functions in osteoclasts and fibroblasts from genetically altered mice. (b) Sky (Tyro 3), a recently discovered, receptor-type protein-tyrosine kinase from the Axl family, that is abundant in normal brain and mouse mammary tumors, and can function in the plasma membrane or cytoplasm. (c) Rlk, a newly discovered member of the Btk/Itk family, expressed exclusively in T cells. (2) Multi-step carcinogenesis. We have used MMTV-Wnt-1 transgenic mice to identify proto-oncogenes (mainly members of the FGF family) and tumor suppressor genes (p53) that influence the rate of progression and the properties of mammary tumors. P53- deficiency promotes genetic instability and histological changes in such tumors, and we are attempting to understand these phenomena by examining apoptosis, cell cycle control, and telomerase activity and by studying MMTV-p53 transgenic mice. (Unexpectedly, mice with a wild type p53 transgene have a developmental defect of the kidney called oligomeganephronia). We are also developing a new multi-step tumor model in transgenic mice by recapitulating the lesions found in human glioblastoma. (3) Wnt gene signaling. We are continuing efforts to identify the elusive receptor(s) for secretory proteins made by the Wnt gene family. In addition, we are examining the roles of vertebrate proteins (especially Disheveled and GSK-3) implicated in Wnt signaling pathways. (4) p16 and melanoma. We are cataloging and characterizing mutant forms of p16, an inhibitor of Cdk/cyclin complexes, that contribute to familial and sporadic melanomas.